[unreadable] Childhood-onset inflammatory bowel disease, Crohn's disease in particular, may be an indicator of increased genetic predisposition leading to a higher penetrance and is often described as having a more severe disease phenotype, i.e. an aggressive or complicated clinical course. Our preliminary results have demonstrated that the presence and magnitude of immune responses to microbial antigens are subclinical markers of a more aggressive clinical phenotype. It is likely than an individual's genetic background and their environment influence the expression of these immune responses, which i [sic] propose in turn alter the natural history of childhood onset Crohn's disease (CD). If indeed these immune responses represent a genetic susceptibility to CD, quantitative and qualitative expression of these immune responses may serve as an immunologic risk marker for CD. In this application I propose that the expression of immune responses in the unaffected parents of CD offspring influence the natural history of childhood-onset CD. The overall objective of this proposal is to determine if there is an association between unaffected parents and their CD offspring for immune response expression and how these associations influence the natural history of childhood-onset CD. The specific aims include Aim 1: To examine the quantitative and qualitative expression of serological immune responses in unaffected parents of offspring with CD and determine if expression in parents is associated with expression in affected offspring and Aim 2: To demonstrate an association between the qualitative and quantitative expression of immune responses in unaffected parents and the natural history of disease in their offspring. 660 unaffected parents will be enrolled and the frequency of immune responses will be determined and tested for associations of their immune responses with those in their offsring [sic] with CD and how the expression of these immune responses influence the natural history of their child's disease. The a priori knowledge of risk factors associated with disease progression, will lead to intervention studies in identified high risk patients with the goal of preventing progression of clinical disease to clinical complication. The results if this study may also identify markers of disease susceptibility, which will enable me to identify high risk individuals and confirm if indeed there are immunological risk markers of disease development and consider intervention studies to prevent pre-clinical disease from becoming clinical disease. The proposed research takes advantage of the fact that the pediatric Crohn's disease population is likely to be a high-risk genetic group with an accelerated natural history. The characterization of the potential risk milieu implied by the presence of immune responses at the sub clinical level in the child's' parents will offer new information on the influence of immune phenotypes on clinical outcomes. [unreadable] [unreadable]